An international research team has identified a candidate “thinness” gene that could help to explain why some people can seemingly stay slim no matter what they eat. A genetic association study that analyzed data from more than 47,000 people in an Estonian biobank implicated ALK as a key gene that may regulate thinness and play a role in resisting weight gain in metabolically healthy thin people. Further studies in animal models showed that deleting ALK resulted in thinner flies and thinner mice, and demonstrated that ALK expression in the brain may be involved in regulating energy expenditure.

ALK is already a recognized anticancer target, and the researchers suggest that targeting the gene may represent a future therapeutic strategy against obesity. “If you think about it, it’s realistic that we could shut down ALK and reduce ALK function to see if we did stay skinny,” said Josef Penninger, PhD, director of the Life Sciences Institute and professor of the department of medical genetics at the University of British Columbia. “ALK inhibitors are used in cancer treatments already. It’s targetable. We could possibly inhibit ALK, and we actually will try to do this in the future.” Penninger is senior author of the team’s published paper in Cell, which is titled, “Identification of ALK in Thinness.” The reported studies involved a multidisciplinary team of researchers in Austria, Switzerland, Estonia, China, Australia, Canada, and Sweden, and the U.S.

There’s considerable variability in how susceptible different people are to putting on weight.  “We all know these people: it’s around one percent of the population,” said Penninger. “They can eat whatever they want and be metabolically healthy. They eat a lot, they don’t do squats all the time, but they just don’t gain weight.”

Body mass index (BMI), which is commonly used to classify weight categories, is a highly complex trait that is impacted by genes and environmental cues, the researchers wrote. And while more than 700 common single nucleotide polymorphisms (SNPs) have been linked with BMI, only a limited number of genes involved in regulating human body weight have been identified and validated. To date, most studies have focused on susceptibility to obesity, and only a few have looked at the genetic basis of thinness in humans or animal models. “Everybody studies obesity and the genetics of obesity,” Penninger pointed out. “We thought, ‘Let’s just turn it around and start a new research field.’ Let’s study thinness.”

To do this Penninger’s team analyzed data from the Estonian Biobank, which includes 47,102 people aged 20–44 years. The investigators carried out a genome-wide association study (GWAS) to compare the DNA samples and clinical data of healthy thin individuals—who were in the lowest 6th percentile—with normal-weight individuals, in the search for genetic variants linked with thinness. Their results highlighted genetic variants in the ALK gene that were specific to the thin individuals.

Scientists have known that the ALK gene frequently mutates in various types of cancer, and while it is viewed as an oncogene that can drive the development of tumors, the role of ALK outside of cancer isn’t understood. “ALK has been extensively studied in cancer, but little is known about the biological role of ALK outside the context of cancer,” they wrote. The new finding suggested that the ALK gene might play a role as a thinness gene involved in weight-gain resistance.

The researchers investigated the association between ALK and thinness through a series of studies in Drosophila fruit flies, and in mice. Their experiments demonstrated that mice in which the ALK gene was knocked out remained thin and were resistant to diet-induced obesity. “Intriguingly, Alk knockout mice were significantly protected against HFD-induced obesity,” the researchers wrote. ALK deficiency was also linked with reduced weight gain in a genetic obesity mouse model. Even when the ALK knockout mice had the same diet and activity levels as normal mice, they still demonstrated lower body weight and body fat from an early age, which persisted into adulthood.

Further studies in mice suggested that ALK, which is highly expressed in the brain, plays a role in instructing the fat tissues to burn more fat from food. “Expression analysis revealed high Alk mRNA levels in the hypothalamus, especially in the PVN, which is also true for humans,” the investigators wrote. “Mechanistically, we found that ALK expression in hypothalamic neurons controls energy expenditure via sympathetic control of adipose tissue lipolysis” … Our genetic and mechanistic experiments identify ALK as a thinness gene, which is involved in the resistance to weight gain.”

The findings could help scientists develop therapeutics against ALK as a future strategy against obesity. The team also plans to further study how neurons that express ALK regulate the brain at a molecular level to balance metabolism and promote thinness.

The Estonian Biobank that the team studied was ideal because of its wide age range and its strong phenotype data. “We took advantage of the wide age range of the unique Estonian biobank recruitment as well as its strong phenotypic datasets, making ECGUT [Estonian Genome Center of the University of Tartu] an ideal starting point to identify potential variants and genes playing a role in thinness,” the scientists noted. Even so, one limitation for replicating these findings is that biobanks that collect biological or medical data and tissue samples don’t have a universal standard in data collection, which makes comparability a challenge. The researchers say they will need to confirm their findings with other data banks through meta-analyses. “You learn a lot from biobanks,” said Penninger. “But, like everything, it’s not the ultimate answer to life, but they’re the starting points and very good points for confirmation, very important links and associations to human health.”

The team suggests its work is unique in its combination of population—and genome-wide-scale analyses into the genetic basis of thinness, with in vivo analyses of gene function in mice and flies. “It’s great to bring together different groups, from nutrition to biobanking, to hardcore mouse and fly genetics,” stated Penninger. “Together, this is one story including evolutionary trees in metabolism, the evolutionary role of ALK, human evidence, and hardcore biochemistry and genetics to provide causal evidence.”

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